2,3,5,6-TETRAHYDROIMIDAZO{8 2,1-b{9 THIAZOLES

ABSTRACT

Substituted imidazo thiazoles, e.g., 3-(4&#39;&#39;-chlorophenyl)-2ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo(2,1-b) thiazole are prepared from 2-haloalkylphenones and 2-imidazolinethione and are useful as anorexics and anti-depressants.

United States Patent Houlihan et al.

[ 51 June 20, 1972 2,3,5,6-TETRAHYDROIMIDAZO[2,1- B ]THIAZOLESInventors:

both of Mountain Lakes, NJ.

Assigneez Sandoz-Wander, lnc., Hanover, NJ.

Filed: Jan. 26, 1970 Appl. No.: 5,894

Related U.S. Application Data Continuation-impart of Ser. No. 790,449,Jan. l0,

1969, abandoned, which is a continuation-in-part of Ser. No. 748,929,July 31, i968, abandoned.

U.S. Cl. ..260/306.7, 260/309.6, 260/590, 424/270 Int. Cl. ..C07d 99/06William J. Houlihan; Robert E. Manning,-

Primary Examiner-Alex Mazel Assistant E.\'aminer--R. J. GallagherAttorney-Gerald D. Sharkin, Frederick H. Weinfeldt, Robert S. Honor,Walter F. Jewell and Richard E. Vila [57] ABSTRACT Substituted imidazothiazoles, e.g., 3-(4'-chlorophenyl)-2- ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo[ 2, l -b ]thiazole are prepared from2-haloalkylphenones and 2-imidazolinethione and are useful as anorexicsand anti-depressants.

10 Claims, No Drawings 2 ,3 ,5 ,6-TETRAHYDROIMIDAZ O[ 2 l-B THIAZOLESThis application is a continuation-in-part of application, Ser. No.790,449 filed Jan. 10, 1969 now abandoned, which in turn is acontinuation-in-part of application Ser. No. 748,929 filed July 3 l1968, now abandoned.

This invention relates to novel heterocyclic compounds. Morespecifically it relates to novel 2-alkyl-3-substitutedphenyl-5,6-dihydroimidazo thiazoles, intermediates therefor, acidaddition salts thereof, and processes for their preparatron.

The thiazoles of the present invention may be represented by the formulai {LN A where each of R R and R independently, represents H or halogenhaving an atomic weight of about 19 to 36, R, represents straight chainlower alkyl, i.e., straight chain alkyl having one to four carbon atomssuch as methyl, ethyl and propyl, provided at least one of R R and R isother than H,

A is H,

B is OH or A and B together represent a carbon to carbon bond. Preferredaspects of this invention are those wherein R, represents methyl orethyl, R represents chloro, R and R represents H, A is H and Brepresents OH.

The process for preparing compounds of formula (1) where A and Brepresent a carbon to carbon bond may be represented as follows:

where R,, R R and R have the above stated significance.

The thiazoles of formula (la) are prepared from the compounds of formula(lb) or an acid addition salt thereof by treatment with an acid such ashydrochloric acid, hyd'robromic acid or acetic acid (preferably aceticacid) at a temperature from about room temperature to about the refluxtemperature of the system, preferably 50 C. to the reflux temperature.The reaction is normally carried out in excess acid, but a solvent maybe used and the particular solvent utilized is not considered critical.Solvents which may be used are lower alkanols such as ethanol,isopropanol and the like, acetone, tetrahydrofuran, or similar inertsolvents.

When the compounds of formula (la) are in the form of acid additionsalts, they may be converted to the free base by conventional methodssuch as suspending the salt form in water and adding sodium carbonate.

' The 3-hydroxy imidazo[2, l -b]thiazoles of formula (lb) may beprepared in acid addition salt form (lc) in accordance with thefollowing reaction scheme:

(III) N-. JL J T L HN NH 1 HX g where R,, R R and R, have the abovestated significance and X is Br or Cl. I

The 3-hydroxy imidazo[2,l-b]thiazoles of formula (lc) are prepared byhalogenating an alkyl phenyl ketone (V), e.g., 4- chlorobutyrophenone,with bromine or chlorine (IV) in an inert solvent such as chloroform,carbon tetrachloride, methylenechloride or the like, at a temperature of0 50 C. (preferably 20 35 C.) for about 1 to 8 hours. The resulting2-haloalkylphenone (III) is treated with 2-imidazolinethione (ll) in aninert solvent such as acetone or lower alkanols having one to fivecarbon atoms, e.g., methanol, ethanol or isopropanol, at a temperatureof 20 -50" C. (preferably 25 35 C.) for about 3 to 48 hours, to give thedesired hydroxy compounds. Standard techniques may be used to recoverthe hydroxy imidazo[2, l -b]thiazoles.

When the salts of formula (lc) above are recovered and it is desired toconvert such salts to the corresponding free bases, conventionaltechniques may be utilized, e.g., dissolution of the salt in water andprecipitation using a base such as sodium hydroxide.

The compounds of formula (lb) may also be illustrated by theirtautomeric equivalents such as represented by the following structuralformula where R,, R R and R, have the above-stated significance, and itshould be appreciated that these tautomers can exist in equilibrium. Thepredominant tautomer is believed to depend on such factors as whetherthe compound is a solid or in solution, and the pH and polarity of theenvironment. In order to simplify this description, however, formula(lb) only will be used, although both tautomeric forms are considered tobe within the concept of the present invention.

It is further recognized that the compounds of formula (lb) exist asgeometric and optical isomers, the separation and recovery of which maybe accomplished employing conventional techniques. All of these isomers(geometric and optical) are included within the scope of this invention.

Certain of the compounds of formula (V) are known and are prepared bymethods disclosed in the literature. Those not specifically disclosedare prepared from known materials using analogous methods.

The compounds of formula (la) and (lb) are useful because they possesspharmacological activity in animals. More particularly, the compoundspossess CNS stimulant activity and are useful as anti-depressants asindicated by their activity in the mouse given parenterally 0.4 25.6mg/kg of body weight of active material. The test method used isbasically as described by Spencer, P.S..l., Antagonism of Hypothermia inthe Mouse by Anit-depressants, in Anti-depressant Drugs, p. 194 204,Eds. S. Garattini and M.N.G. Dukes, Excerpta Medica Foundation, 1967.

The compounds of formulas (la) and (lb) are also useful as anorexics asindicated by their activity in rat given 10 to 50 mg/kg of activematerial and tested by use of the free feeding method described byRandall, et al. (J.P.E.T., 129, 163, 1960) whereby 16 groups of six maleWistar rats are deprived of food for 18 hours but receive water adlibitum. Consumption of ground food is then measured over a four hourperiod following oral administration of the active compound.

Additionally, the compounds of formula (lb) are useful as diuretics asindicated by their activity in unanesthetized rat given 6.25 50 mg/kgand tested using basically the method described by R. Aston (Toxicol.and Appl. PharmacoL, 1:277, 1959).

For such uses, the compounds (la) or (lb) may be combined with apharmaceutically acceptable carrier or adjuvant, and mat be administeredorally in such forms as tablets, capsules, elixirs, suspensions and thelike, or parenterally in the form of an injectable solution orsuspension. The dosage will vary depending upon the mode ofadministration utilized and the particular compound employed.

These compounds of formulas (la) and (lb) may be similarly administeredin the form of their non-toxic pharmaceutically acceptable acid additionsalts. Such salts possess the same order of activity as the free base,are readily prepared by reacting the base with an appropriate acid andaccordingly are included within the scope of the invention.Representative of such salts are the mineral acid salts, such as thehydrochloride, hydrobromide, sulfate, phosphate and the like and theorganic acid salts, such as the maleate, fumarate, tartrate, citrate,succinate, ben zoate, acetate, p-toluenesulfonate, benzenesulfonate andthe like.

In general, satisfactory results for anorexic or anti-depressantactivity are obtained when the compounds are administered at a dailydosage of from about 0.1 to 50 milligrams per kilogram of animal bodyweight. This daily dosage is preferably given in divided doses, e.g., 2to 4 times a day, or in sustained release form. For most large animals,the total daily dosage is from about 6 to 300 milligrams and dosageforms suitable for internal administration comprise from about 1.5 to150 milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent.

For the diuretic use, the compounds (lb) may be administered at a dailydosage of from about 1 milligrams per kilogram of animal body weight,preferably given 2 4 times a day or in sustained release form. For mostlarge animals, the total daily dosage is from about 50 500 milligrams,and dosage forms suitable for internal administration comprise fromabout 12.5 250 milligrams of compound (lb) in admixture with a solid orliquid pharmaceutical carrier or diluent.

A representative formulation suitable for oral administration is atablet prepared by standard tabletting techniques.

which contains the following:

Ingredient Parts by Weight 3-( 4 '-chlorophenyl )-2-ethyl-3-hydroxy-2,3,5,-tetrahydroimidazol2,l-b ]thiazole tragacanth 2 lactose 79-.5 cornstarch 5 talcum 3 magnesium steurate 0.5

EXAMPLE 1 .HBr

A flask (equipped with a stirrer and dropping funnel) is charged with 54g (0.30 mole) of 4-chlorobutyrophenone and 250 ml of chloroform. Thesolution is stirred and a solution of 48.0 g (16.0 ml, 0.3 mole) ofbromine and 250 ml of chloroform is added dropwise at a rate such thatthe internal flask temperature does not exceed 35 C. The resultingsolution is stirred for one hour and the solvent removed in vacuo. Theresidue is dissolved in 150 ml of isopropanol and added in one portionto a slurry of 30.6 g (0.30 mole) of 2- imidazolinethione and 500 ml ofisopropanol. The reaction is exothermic and a solution results. In about1 hour a solid comes out of solution. Stirring is continued for 24 hoursat room temperature at which time the resultant solid is filtered off togive 3(4'-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5.6-tetrahydroimidazo[2,1-b]thiazole hydrobromide; m.p. 280- 283 C.

This compound has been found to have lipolytic activity and may be usedto treat obesity or.as a weight reducing agent as indicated by itsactivity in rats given 10 f 37.5 mg/kg of compound and tested asindicated by Dole et al (J. Biol. Chem. 235; 2595, 1960). This compoundproduces satisfactory results for this use when administered at a dailydosage of from about 0.5 37.5 mg/kg of animal body weight. For largeanimals, dosages of 15 150 mg/day are satisfactory and dosage forms maycontain about 3.75 75 milligrams of the compound in conjunction withpharmaceutical carrier.

CH3CH2 EXAMPLE 2 3 4'-Chlorophenyl )-2-ethyl-5 ,6-dihydroimidazo[2,1- b]thiazole hydrobromide .HBr CHJCHE A mixture of 30 g of3-(4-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo[ 2, l-b]thiazole hydrobromide and 250 ml acetic acid is refluxed for 15hours. The solvent is then removed in vacuo and the residue is stirredwith ml of isopropanol. The solid is filtered off to give 3(4'-chlorophenyl )-2-ethyl-5 ,-dihydroimidazo [2,l-b1thiazole hydrobromide;m.p. 281- 284 C.

EXAMPLE 3 3-(4-Chlorophenyl)-3-hydroxy-2-methyl-2,3,5 ,6-tetrahydroimidazo[ 2, l -b ]thiazole hydrobromide A flask (equipped witha stirrer and dropping funnel) is charged with 54 g (0.30 mole) of4-chloropropiophenone and 250 ml of chloroform. The solution is stirredand a solution of 48.0 g (16.0 ml, 0.3 mole) of bromine and 250 ml ofchloroform is added (dropwise) at a rate such that the internal flasktemperature does not exceed 35 C. The resulting solution is stirred for1 hour and the solvent removed in vacuo. The resulting solution isstirred for 1 hour and the solvent removed in vacuo. The residue isdissolved in 150 ml of isopropanol and added in one portion to a slurryof 30.6 g (0.30 mole) 2-imidazolinethione and 500 ml of isopropanol. Thereaction is exothermic and a solution results. In about 1 hour a solidcomes out of solution. Stirring is continued for 24 hours at roomtemperature at which time the resultant solid is filtered off to give3-(4-chlorophenyl)- 3-hydroxy-2-methyl-2,3,5,6-tetrahydroimidazo[2,1-b]thia2ole hydrobromide; m.p. 171 172 C.

This compound also has lipolytic activity and may be used to treatobesity at the same dosage levels as the compound of Example 1.

When the above process is carried out and 4-fluorobutyrophenone,3,4'-dichlorobutyrophenone, 3-ch1orobutyrophenone,4-ch1orovalerophenone, or 4-ch1orohexanophenone is used in place of4'-chloropropiophenone, there is obtained2-ethyl-3-(4-fluorophenyl)-3-hydroxy-2,3,5,6- tetrahydromidazo[2,l]thiazole hydrobromide (m.p. 165166 C. 3-(3'-dichlorophenyl)-2-ethyl-3-hydroxy- 2 ,3 ,5 ,6-tetrahydroimidazo[ 2, 1-b]thiazole hydrobromide (m.p. l77178 C.),3-(3'-chlorophenyl)-2-ethy1-3-hydroxy- 2 ,3 ,5 ,6-tetrahydroimidazo[ 2,l -b]thiazole hydrobromide (m.p. l79180 C.),3-(4'-chlorophenyl)-3-hydroxy-2-npropy1-2,3 ,5 ,6-tetrahydroimidazo[ 2,1 -b]thiazole hydrobromide (m.p. 253-255 C.), or2-n-butyl-3-(4'-chlorophenyl)- 3-hydroxy-2,3 ,5 ,6-tetrahydroimidazo[ 2,l -b ]thiazole hydrobromide (mp. 7l 58 C. respectively.

EXAMPLE 4 3-(4'-Ch1orophenyl)-2-methyl-5,6-dihydroimidazo[2,1-

b]thiazole hydrobromide IT J l N EXAMPLE 53-(4'-ch1orophenyl)-2-ethy1-3-hydroxy-2,3,5,6- tetrahydroimidazo[ 2, 1e-blthiazole A solution of 45 g of3-(4'-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole hydrobromide in 250 ml of water is added to a stirredand ice cooled solution of g of sodium hydroxide in 250 ml of water.After 1.5 hours stirring the resultant solid is filtered off to give3-(4- chlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6- tetrahydroimidazo[2, le-b]thiazo1e; m.p. l65l 66 C.

EXAMPLE 6 3-(4'-ch1orophenyl)-2-ethy1-3-hydroxy-2,3,5,6-tetrahydroimidazo[ 2, l e-b] thiazole maleate To a stirred solution of5.8 g. (0.05 mole) of maleic acid in 100 ml of methanol there is addeddropwise in 0.3 hour a solution of 14.1 g (0.05 mole) of3-(4-chlorophenyl)-2-ethyl-3- hydroxy-2,3,5,6-tetrahydroimidazo[2,l-b]thiazole in 400 ml of methanol. After stirring one hour the solutionis concentrated in vacuo to about one-third of the original volume,treated with 300 ml of diethyl ether and then cooled in an ice bath toobtain 3-(4-ch1orophenyl)-2-ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo[2, l e-b]thiazole maleate; mp 89 92 C.

When the above process is carried out and fumaric acid, tartaric acid,hydrochloric acid or citric acid is used in place of maleic acid, thecorresponding fumarate (mp 270 272 C.); tartrate (mp 128 130 C.),hydrochloride (mp 270 -272 C.) or citrate (mp 146 147 C.) respectively,is obtained.

What is claimed is:

1. A compound of the formula wherein R represents methyl apharmacologically acceptable acid addition salt thereof.

4. The compound of claim 1 which is 3-(4-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5 ,6-tetrahydroimidazo[ 2, l -b]thiazole.

5. The compound of claim I which is 3-(4'-chlorophenyl)-3-hydroxy-2-methyl-2.3,5,6-tetrahydroimidazoI 2. l-b] thiazole.

6. The compound of claim 1 which is 2-ethyl-3-(4- fluorophenyl)-3-hydroxy-2,3,5 ,6-tetrahydroimidazo[2,1-b] thiazole.

7. The compound of claim I which is 3-(3 ',4'-dichlorophenyl)-2-ethyl-3-hydroxy-2,3 ,5 ,6-tetrahydroimidazo[ 2, l b]thiazole.

8. The compound of claim 1 which is 3-(3-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole.

9. The compound of claim 1 which is 3-(4-chlorophenyl)-3-hydroxy-2-n-propyl-2,3,5 ,6-tetrahydroimidazo[ 2, 1 -b] thiazole.

10. The compound of claim 1 which is 2-n-butyl-3-(4- chlorophenyl)-3-hydroxy-2,3,5 ,G-tetrahydroimidazo 2, l -b] thiazole.

2. A compound according to claim 1 of the formula
 3. A compoundaccording to claim 1 of the formula
 4. The compound of claim 1 which is3-(4''-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 5. The compound oF claim 1 which is3-(4''-chlorophenyl)-3-hydroxy-2-methyl-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 6. The compound of claim 1 which is2-ethyl-3-(4''-fluorophenyl)-3-hydroxy-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 7. The compound of claim 1 which is3-(3'',4''-dichlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 8. The compound of claim 1 which is3-(3''-chlorophenyl)-2-ethyl-3-hydroxy-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 9. The compound of claim 1 which is3-(4''-chlorophenyl)-3-hydroxy-2-n-propyl-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 10. The compound of claim 1 which is2-n-butyl-3-(4''-chlorophenyl)-3-hydroxy-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.